The nuclear coactivator binding domain (NCBD) of transcriptional co-regulator CREB-binding protein (CBP) is an example of conformationallym alleable proteins that can bind to structurally unrelated protein targets and adopt distinct folds in the respective protein complexes. Here, we show that the folding landscape of NCBD contains an alternative pathwayt hat resultsi np rotein aggregation and selfassembly into amyloid fibers. The initial steps of such protein misfolding are driven by intermolecular interactions of its N-terminal a-helix bringing multiple NCBD molecules into contact. These oligomers then undergo slow but progressive interconversion into b-sheet-containing aggregates.T o reveal the concealed aggregation potentialo fN CBD we used ac hemically synthesized mirror-image d-NCBD form. The addition of d-NCBD promoted self-assembly into amyloid precipitates presumably due to formation of thermodynamically more stable racemic b-sheet structures. The unexpecteda ggregation of NCBD needs to be taken into considerationg iven the multitude of protein-protein interactions and resulting biological functions mediated by CBP.

Bicycloalkanes are well‐known isosteres of alkynes and aromatic rings and their use in the field of medicinal chemistry and drug discovery has been on the rise in the past ten years. Herein, we report the modular and practical synthesis of bicycloalkane‐containing fragments using nickel‐photoredox catalysis. The comparison of their relevant physical‐chemical properties with their aromatic counterparts shows a substantial improvement in LogP and aqueous solubility for bicyclo[1.1.1]pentane derivatives, but not for bicyclo[2.2.2]octane derivatives.

Aggregation and self‐assembly of nuclear coactivator binding domain of CREB‐binding protein was studied under different experimental conditions. Single l‐ or d‐enantiomers fold into left‐ or right‐handed helical structures at neutral pH while β‐sheet amyloid arrangement occurs under acidic conditions. Mixtures of both enantiomers promote self‐assembly into amyloid β‐sheet structures highlighting the role of chirality in the formation of thermodynamically more stable racemic β‐sheet structures. Fore more information, see the Full Paper by V. Torbeev et al. on page 9889 ff.